高效多肽疫苗激活T细胞抗肿瘤的复合物结构研究及分子机制

项目名称： 高效多肽疫苗激活T细胞抗肿瘤的复合物结构研究及分子机制

项目编号： No.31470738

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 殷雷

作者单位： 武汉大学

项目金额： 90万元

中文摘要： T细胞有着很强的识别多肽抗原和杀伤肿瘤细胞的能力。当前通过多肽疫苗激活人体T细胞去攻击肿瘤细胞正受到广泛研究。然而其中的一个主要瓶颈在于激发的免疫强度不够。我们选取小鼠结肠癌模型中一组比肿瘤抗原母体多肽疫苗疗效高很多的模拟多肽疫苗作为研究对象。这些多肽疫苗先结合在MHC（主要组织相容性复合体）分子Ld上，然后被肿瘤特异性TCR（T细胞受体）识别。我们的初步试验结果提示，高效的模拟多肽疫苗能被TCR两步识别，从而加强了免疫识别和应答。这种多肽疫苗识别中的新现象，突破了原有的认识，大大深化了对多肽疫苗识别的理解。Ld/多肽疫苗结构数据也表明模拟多肽上存在的构象变化可能与此相关。我们将进一步开展多个TCR/多肽疫苗/Ld三元复合物的结构研究，同时也将分析TCR上关键残基突变对多肽疫苗识别的动力学影响和对T细胞激活的影响，提出模拟多肽疫苗优化的相关理论和法则并指导设计新的肿瘤多肽疫苗。

中文关键词： T细胞受体；分子识别；多肽疫苗；主要组织相容性复合物；蛋白质结构

英文摘要： T cell is very powerful at recognition of peptide antigens and killing of abnormal cells. Nowadays it is under intensive researches to use peptide vaccines to stimulate endogenous T cells to attack tumors. However, one of the major bottle necks is the weak stimulation of T cells. We focus on a set of peptide variants which are more effective in vaccines in a mouse colon tumor model than the wildtype peptide from the tumor antigen. These peptide vaccines will bind to the relevant MHC(Major Histocompatibility Complex) molecule, Ld, and be recognized by tumor specific TCR(T Cell Receptor). The data of the binding kinetic by the TCR indicats that the effective peptides variant could go through two phase recognition by the TCR to enhance the recognition. It was not reported before in the field of tumor peptide vaccine recognition and will greatly widen our knowledge. The complex structures of Ld/peptide also suggest that the conformational change of the peptide might be responsible for the two phase recognition by the TCR. We would like to keep forward to solve several complex structurs of the TCR binding to Ld/peptide to see how TCR recognizes the Ld/peptide vaccine.We also want to combine the study of mutations on the TCR to see how the important residues determine the effective TCR recognition and T cell stimulation. It is our final goal to understand the mechanism and principle of how tumor peptide vaccines can stimulate T cells effectively and to design effective peptide vaccines based on that.

英文关键词： T cell receptor;molecular recognition;peptide vaccine;MHC;protein structure